new directions for oral treatment in b-cell malignancies · 2020. 8. 18. · oral therapy for the...

New Directions for Oral Treatment in B-Cell Malignancies

Implications for Pharmacists

This educational activity is accredited by Purdue University, sponsored by Postgraduate Healthcare Education, LLC,

and supported by educational grants from AbbVie Inc. and Janssen Pharmaceuticals Inc.

Anthony J. Perissinotti, PharmD, BCOPClinical Team Lead, Hematology/Oncology Clinical Pharmacist Specialist, Inpatient HematologyThe University of Michigan – Michigan MedicineAdjunct Clinical Assistant ProfessorThe University of Michigan College of PharmacyAnn Arbor, MI

Dr. Perissinotti is a hematology clinical pharmacist specialist at the University of Michigan, Michigan Medicine, clinical team leader of hematology/oncology, and adjunct clinical assistant professor at the University of Michigan College of Pharmacy in Ann Arbor, Michigan. He obtained his Doctor of Pharmacy degree from Wayne State University in Detroit, Michigan. He completed his first year of postgraduate residency training at the Detroit Medical Center, Harper University Hospital in Detroit, and his second year of postgraduate residency training at The University of Texas MD Anderson Cancer Center in Houston, Texas. Dr. Perissinottti is a Board Certified Hematology/Oncology Pharmacist.

Faculty

Victoria Nachar, PharmD, BCOPClinical Pharmacist Specialist, Ambulatory Hematology OncologyUniversity of Michigan – Michigan Medicine,Rogel Cancer CenterAdjunct Clinical Assistant ProfessorThe University of Michigan College of PharmacyAnn Arbor, MI

Dr. Nachar is a hematology/oncology clinical pharmacist specialist at the Michigan Medicine RogelCancer Center and an adjunct clinical assistant professor at the University of Michigan College of Pharmacy. She completed her Doctor of Pharmacy degree at the University at Buffalo, followed by residency training at the University of Michigan. She is a Board Certified Hematology/Oncology Pharmacist. She primarily cares for patients with both hematological and oncologic malignancies in Ann Arbor and at the Rogel Cancer Center satellite in Brighton, Michigan. Her professional interests include lymphoma, multiple myeloma, and clinical research.

Faculty

Disclosures

Drs. Perissinotti and Nachar have disclosed that they have no actual or potential conflict of interest in relation to this program.

The clinical reviewer, Ashley Glode, PharmD, BCOP, has no actual or potential conflict of interest in relation to this program.

Susanne Batesko, RN, BSN, Robin Soboti, RPh, and Susan R. Grady, MSN, RN-BC, as well as the planners, managers, and other individuals, not previously disclosed, who are in a position to control the content of Postgraduate Healthcare Education (PHE) continuing education activities hereby state that they have no relevant conflicts of interest and no financial relationships or relationships to products or devices during the past 12 months to disclose in relation to this activity. PHE is committed to providing participants with a quality learning experience and to improve clinical outcomes without promoting the financial interests of a proprietary business.

Accreditation

Purdue University is accredited by the

Accreditation Council for Pharmacy Education

as a provider of continuing pharmacy

education.

UAN: 0018-9999-20-020-H01-P

Credits: 1.0 hour (0.1 CEU)

Type of Activity: Application

Learning Objectives

• Discuss the current guideline recommendations for the treatment of B-cell malignancies

• Appraise the mechanism of action, efficacy, and safety of current and emerging oral treatment options for B-cell malignancies

• Demonstrate strategies to effectively counsel patients receiving oral therapy for the treatment of B-cell malignancies, including assessment and management of adverse effects, and education for promoting safe use and adherence to treatment

Hardy RR, Hayakawa K. B cell development pathways. Annu Rev Immunol. 2001;19:595-621.

BLOOD AND MARROW

Lymphoid progenitor

Pre-B-cell

Naïve B-cell

Activated B-Cell

Germinal center B-cell

Memory B-cell

Plasmablast

Plasma cell

SECONDARY LYMPHOID

TISSUE

BONE MARROW

Acute lymphoblastic leukemia

Mantle cell lymphoma (MCL), Marginal zone lymphoma (MZL),

Chronic lymphocytic leukemia (CLL)

Follicular lymphoma (FL)

Burkitt lymphoma, CLL

Waldenstrom’s macroglobulinemia (WM)

Multiple myeloma,Amyloidosis

Diffuse large b-cell lymphoma (DLBCL)

B-Cell Malignancy Cell of Origin

B-Cell Non-Hodgkin Lymphoma (NHL)

MCLFL, CLL, MZL, WM

Indolent Very AggressiveFeatures of both Aggressive Very aggressive

DLBCLBurkitt

lymphomaHigh grade, NOS

(i.e., “double hit”)

Survival prognosis: years to decadesGoal: disease control

Survival prognosis: months to years Goal: cure

Survival prognosis: yearsGoal: disease control

Al-Hamadani M, et al. Am J Hematol. 2015;90(9):790-5.; Siegel RL, et al. CA Cancer J Clin. 2020;70(1):7-30.

Therapies in B-Cell Malignancies

B-cell receptorCD20

B-cell malignancy

BAX

BAK

Cellnucleus

BCL2

BTK

PI3K

Anti-CD20 monoclonal antibodies1. Rituximab2. Obinutuzumab3. Ofatumomab

Traditional chemotherapy1. Alkylating agents

• Cyclophosphamide, chlorambucil, bendamustine

2. Purine/pyrimidine analogues• Fludarabine, bendamustine, cytarabine

3. Anthracyclines• Doxorubicin

4. Vinca alkyloids (microtubule inhibitor)• Vincristine

BTK inhibitors1. Ibrutinib2. Acalabrutinib3. Zanubrutinib

BCL2 inhibitor1. Venetoclax

PI3K inhibitors1. Idelalisib2. Duvelisib3. Copanlisib

Ongoing studies to determine optimal sequence or combinations

Variety of standard regimens

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas v1.2020.

Regimen Definitions

FCR

Clb + Obi

BR

HiDAC

Nordic regimen

CHOP

Hyper-CVAD

Fludarabine, cyclophosphamide, rituximab

Chlorambucil, obinutuzumab

Cyclophosphamide, doxorubicin, vincristine, prednisone

High-dose cytarabine

Maxi-CHOP alternating with HiDAC

Bendamustine, rituximab

Cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with HiDAC, methotrexate

CVP

DRC

VR-CAP

BDR

Bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone

Cyclophosphamide, vincristine, prednisone

Dexamethasone, rituximab, cyclophosphamide

Bortezomib, dexamethasone, rituximab

CVP Cyclophosphamide, vincristine, prednisone

Chronic Lymphocytic Leukemia (CLL)

• Indolent lymphoma

• Incidence:• Estimated 21,040 Americans in

2020

• Deaths:• 4060 in 2020

• Median age: 70 years

National Cancer Institute. seer.cancer.gov/statfacts/html/clyl.html. Accessed June 2nd, 2020.; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma v4.2020.; Siegel RL, et al. CA Cancer J Clin. 2020;70(1):7-30.

• Most prevalent leukemia

• Prognostic factors:• del(17p)/TP53 mutation, unmutated

IGHV, complex karyotype

• CLL and SLL (same malignancy)• CLL: > 5000 clonal lymphocytes in blood

• SLL: < 5000 clonal lymphocytes in blood but presence of lymphadenopathy and/or splenomegaly

IGHV, immunoglobulin heavy chain variable.

First-Line Treatment in CLL:Pre-BTK Inhibitors

New standardOld standardPopulation

Young/fit

Older/fit

Elderly/comorbidities

Mutated IGHV: FCR Unmutated IGHV: FCR

or BR

Chlorambucil + Obi

Bendamustine + rituximab

BTK Inhibitor Mechanism of Action

Marini BL, et al. J Oncol Pharm Pract. 2017;23(7):502-17.

BCR

LYN

SYK

CD

79

a

CD

79

b

BTK

PLCγ2

PKC

MAPK/MEK/ERKpathway

NF-kβpathway

BTK inhibitor

ECOG 1912 Trial: Study Schema

Shanafelt TD, et al. N Engl J Med. 2019;381(5):432-43.

Ibrutinib + rituximabIbrutinib 420 mg PO daily cycles 1-7

Rituximab cycles 2-7

FCRx 6 cycles

Standard CLL dosing

n = 354

n = 175

Population• Treatment-naïve CLL• Age ≤ 70 years,

ECOG 0-2• Del(17p) excluded

Ibrutinib maintenance

Randomized 2:1

Study design

• Phase III, multicenter, open-label, randomized controlled trial (RCT)

Primary outcome

• Progression-free survival (PFS)

ECOG 1912 Trial: ResultsIbrutinib + Rituximab (IR) vs. FCR

IR improved PFS vs. FCR, especially in IGHV unmutated CLLConclusions

PFS

Years40 1 2 3

PFS

(%

)

1.0

0.8

0.6

0.4

0.2

0

P < 0.001

Ibrutinib + RituximabFCR

89.4%

72.9%

40 1 2 3

PFS

(%

)

1.0

0.8

0.6

0.4

0.2

0

Years

PFS (IGHV unmutated)

P < 0.001

90.7%

62.5%

Ibrutinib + RituximabFCR

Shanafelt TD, et al. N Engl J Med. 2019;381(5):432-43.


or BR

Chlorambucil + Obi


First-Line Treatment in CLL:Changing Landscape


Young/fit

Older/fit


Ibrutinib + rituximab*

*Mutated IGHV without del(17p)/TP53 mutation can consider FCR.

Alliance A041202 Trial: Study Schema

Study design

• Phase III, multicenter, open-label, RCT

Primary outcome

• PFS

Ibrutinib + rituximabIbrutinib 420 mg PO daily cycles 1-6

Rituximab cycles 2-6

Bendamustine/rituximab(BR) x 6 cyclesStandard CLL dosing

n = 182

n = 183

Population• Treatment-naïve CLL• Age ≥ 65 years• ECOG 0-2• Del(17p) NOT excluded


Randomized 1:1:1

IbrutinibIbrutinib 420 mg PO daily


Cross-over allowed

n = 182

Woyach JA, et al. N Engl J Med. 2018;379(26):2517-28.

Alliance A041202 Trial: ResultsIbrutinib + Rituximab (IR) vs. Ibrutinib Alone vs. Bendamustine + Rituximab (BR)

Median PFS 2-Yr PFS

Ibrutinib Not reached 87%

Ibrutinib + R Not reached 88%

BR 43 months 74%

PFS

(%

)

100

80

60

40

20

0

Months

0 6 12 18 24 30 36 42 48

Ibrutinib ± rituximab improved PFS vs. BR

Conclusions

Vast majority of patients with CLL no longer need chemotherapy

No improvement with adding rituximab to ibrutinib

P < 0.001

Woyach JA, et al. N Engl J Med. 2018;379(26):2517-28.


or BR

Chlorambucil + Obi



Young/fit

Older/fit



Ibrutinib

*Mutated IGHV without del(17p)/TP53 mutation can consider FCR; can consider no rituximab with ibrutinib based on ALLIANCE trial (but now FDA approved).

First-Line Treatment in CLL:

Changing Landscape

FDA, United States Food and Drug Administration.

BTK Inhibitors Not Created Equal

IC50/EC50 (nM)

Kaptein A, et al. Blood. 2018;132(Suppl 1):1871.

Kinase Ibrutinib Acalabrutinib Zanubrutinib

BTK 1.5 5.1 0.5

TEC 10 126 44

ITK 4.9 > 1000 50

BMX 0.8 46 1.4

EGFR 5.3 > 1000 21

ERBB4 3.4 16 6.9

JAK3 32 > 1000 1377

BLK 0.1 > 1000 2.5

ELEVATE-TN Trial: Study Schema

Study design


Primary outcome

• PFS

Acalabrutinib + obinutuzumab

Acalabrutinib 100 mg PO q12hObinutuzumab cycles 2-6

Obinutuzumab +chlorambucil

Standard CLL dosing

n = 179

n = 177

Population• Treatment-naïve CLL• Age ≥ 65 or < 65 years

with comorbidities

Acalabrutinibmaintenance

Randomized 1:1:1

AcalabrutinibAcalabrutinib 100 mg PO q12h

Acalabrutinibmaintenance

Cross-over allowed

n = 179

Sharman JP, et al. Lancet. 2020;395(10232):1278‐91.

Sharman JP, et al. Lancet. 2020;395(10232):1278‐91.

100

80

60

40

20

0

PFS

(%

)

0 6 12 18 24 30 36

Months

Acalabrutinib + obininutuzumabAcalabrutinibChlorambucil + obinutuzumab

40

Acalabrutinib ± Obi improved PFS vs. chlorambucil + Obi

Conclusions

Higher ORR with adding Obi to acalabrutinib (94% vs. 79%; p<0.0001)

No significant PFS improvement with adding Obi to acalabrutinib

90%

82%

34%

ORR, overall response rate.

ELEVATE-TN Trial: ResultsAcalabrutinib + Obinutuzumab vs. Acalabrutinib Alone vs. Chlorambucil + Obinutuzumab

BCL2 Inhibitor Mechanism of Action

BAK

BAX

BAX

BAK

Caspase-dependent apoptosis

BCL-2

BCL-2

Anderson MA, et al. Semin Hematol. 2014;51(3):219-27.

BH3 proteins(e.g., BIM, BAD, PUMA, NOXA) Venetoclax

Anti-apoptotic proteins(BCL-2, MCL1, BCLXL, etc.)

BCL2 overexpression:

binds to BAX and BAK

preventing apoptosis

BAX

BAK

BAX

BAKVenetoclax

CLL14 Trial: Study Schema

Venetoclax + obinutuzumabVenetoclax ramp-up day 22 of cycle 1 (continue until

cycle 12 complete)Obinutuzumab x 6 cycles

Chlorambucil + obinutuzumabChlorambucil 0.5 mg/kg days 1, 15

x 12 cyclesObinutuzumab x 6 cycles

n = 216

n = 216

Population• Treatment-naïve CLL• Patients with significant

comorbidities (a total score of > 6 on the Cumulative Illness Rating Scale) or CrCl < 70 mL/min

Randomized 1:1

Study design


Primary outcome

• PFS

Fischer K, et al. N Engl J Med. 2019;380(23):2225‐36. CrCl, creatinine clearance.

CLL14 Trial: ResultsVenetoclax + Obinutuzumab vs. Chlorambucil + Obinutuzumab

Venetoclax ± Obi improved PFS vs. chlorambucil + Obi

Conclusions

Low rate of tumor lysis; no different between the 2 groups

Provides a targeted therapy option with a fixed duration (1 year then stop)P

FS (

%)

100

80

60

40

20

00 6 12 18 24 30 36

Months

64%

88%

Venetoclax + obinutuzumabChlorambucil + obinutuzumab

Fischer K, et al. N Engl J Med. 2019;380(23):2225‐36.


or BR

Chlorambucil + Obi



Ibrutinib


Young/fit

Older/fit

Elderly/comorbiditiesAcalabrutinib +/- Obi

IbrutinibVenetoclax + Obi

*Mutated IGHV without del(17p)/TP53 mutation can consider FCR; can consider no rituximab with ibrutinib based on ALLIANCE trial (but now FDA approved).

First-Line Treatment in CLL:

Changing Landscape

Mantle Cell Lymphoma (MCL)

• Hallmark: • t(11;14)

• Prognostic factors:• p53 mutations, ATM, CCND2 or 3, SOX11, IGHV

• Cytologic variants• Classic, small-cell, blastoid, pleomorphic

Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16(8):2780-95.; Eskelund CW, et al. Blood. 2017;130(17):1903-10.; Herrmann A, et al. J Clin Oncol. 2009;27(4):511-8.; Hoster E, et al. Blood. 2008;111(2):558-65.; Jain P, Wang M. Am J Hematol. 2019;94(6):710-25.; National Cancer Institute. seer.cancer.gov/statfacts/html/nhl.htm. Accessed June 2, 2020.; National Comprehensive Cancer Center. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas v1.2020.; Tiemann M, et al. Br J Haematol. 2005;131(1):29-38.

• Indolent with aggressive features

• Incidence: 6% of NHL

• Deaths:• Low risk: 5-year OS 60%

• Intermediate risk: median 51-month OS

• High risk: median 29-month OS


OS, overall survival.

MCL Treatment 2020

NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas v1.2020.

First-line therapy

Transplant eligible Non-transplant eligible

Intensive therapyR-CHOP/HiDAC-based

therapy (i.e., Nordic, Hyper-CVAD)

Less intensive therapyBR, R-CHOP, VR-CAP,

R-lenalidomide

Autologous stem cell transplant

Maintenance rituximab

“Watch and wait”/observation

Relapsed/refractory therapy

Second line:• R-chemotherapy• Bortezomib ± R• Lenalidomide ± R• BTK inhibitors:

• Ibrutinib ± R• Acalabrutinib• Zanubrutinib

• Venetoclax ± ibrutinib

Third line:• Treatment based on prior

therapiesFactors to consider: response and duration of response to previous therapy, patient age, and comorbidities.

Ibrutinib Pooled Analysis: Relapsed/Refractory (R/R) MCL

Rule S, et al. Haematologica. 2019;104(5):e211-4.

Phase 2 PCYC-1104

Phase 2 SPARK

Phase 3 RAY

Ibrutinib 560 mg PO daily became an option for R/R MCL

Led to FDA approval in

MCL

PFS100

80

60

40

20

00 4 12 20 28 36 44 52 60 68 76

Months

PFS

(%

)

Median: 25.4 months

Median: 10.3 months1 prior line> 1 prior line

ACE-LY-004 Trial: Study Schema

Study design

• Phase II, multicenter, open-labeI

Primary endpoint

• ORR

Wang M, et al. Lancet. 2018;39(10121)1:659-67.

Acalabrutinib100 mg PO BID in 28-day cycles

Until progression or unacceptable toxicity

*class 3/4 cardiac disease per NYHA Functional Classification, CHF or MI within 6 months of screening, QTc > 480 ms, uncontrolled/symptomatic arrhythmias.

n = 124

Population• R/R MCL• 1-5 prior lines of therapy• No notable CVD*• No concurrent use of

warfarin/equivalent vitamin K antagonists

• No prior BTK or BCL-2 inhibitors

CHF, congestive heart failure; CVD, cardiovascular disease; MI, myocardial infarction; NYHA, New York Heart Association.

ACE-LY-004 Trial:Acalabrutinib for R/R MCL Results

Wang M, et al. Lancet. 2018;391(10121):659-67.; Wang M, et al. Leukemia. 2019;33(11):2762‐6.

81% ORR

0

20

40

60 43% CR

38% PR

80

100

Median duration of response: 26 monthsEstimated 24-month OS: 72.4% (median OS not reached)

1.0

0.8

0.6

0.4

0.2

0

PFS

%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Led to FDA approval in MCL

Median PFS: 20 months

Months

Res

po

nse

(%

)

Ibrutinib or acalabrutinib now options for R/R MCL

CR, complete response; PR, partial response.

BCG-3111-206 Trial: Study Schema

Song Y, et al. Clin Cancer Res. 2020;clincanres.3703.2019.

Zanubrutinib160 mg PO BID in 28-day cycles


*Clinically significant CVD; patients with history of cardiac arrythmia that was adequately controlled at time of enrollment were eligible

n = 86

Population• R/R MCL• 1-4 prior lines of

treatment• No notable CVD*• No prior BTK inhibitors

Study design


Primary endpoint

• ORR

BCG-3111-206 Trial:Zanubrutinib for R/R MCL Results

83.7% ORR

0

20

40

60

68.6% CR

15.1% PR

80

100

Re

spo

nse

(%

)

Led to FDA approval in MCL

Ibrutinib, acalabrutinib, or zanubrutinibnow options for R/R MCL

0 6 12 18 24

Months

PFS

(%

)

Median PFS: 22.1 months

100

80

60

40

20

0

Song Y, et al. Clin Cancer Res. 2020;clincanres.3703.2019.

M12-175 Trial: Study Schema

VenetoclaxDose escalation study (3+3

design) to target daily dose of 200-1200 mg orally daily


n = 28

Population• R/R MCL• 1-7 prior lines of

treatment (median 3)• No prior BTK inhibitors or

lenalidomide

Study design

• Phase I multicenter, open-labeI

Primary endpoint

• Safety

Davids MS, et al. J Clin Oncol. 2017;35(8):826-33.

Venetoclax: R/R MCL

75% ORR

0

20

40

60 21% CR

54% PR

80 100

75

50

25

6 12 18 24 30 36 42 48P

FS (

%)

Time (months)

Estimated median PFS: 14 months

Davids MS, et al. J Clin Oncol. 2017;35(8):826-33.

Future Directions: AIM TrialIbrutinib + Venetoclax for R/R MCL

Ibrutinib560 mg PO daily

for 4 weeksUntil

progression or

unacceptable toxicity

n = 24

Population• R/R MCL or treatment-

naïve not candidate for chemoimmunotherapy

• No notable CVD*• No prior BTK inhibitors

*Uncontrolled or symptomatic arrhythmias, CHF, or MI within 6 months of screening, or any class 3/4 cardiac disease per NYHA Functional Classification.

Study design

• Phase 2, multicenter, open-labeI

Primary endpoint

• CR at week 16


Venetoclax400-800 mg PO

daily

50 mg

100 mg

200 mg

400 mg

800 mg

Dose increased weekly to 400 mg; increased to 800 mg if no CR by week 16.

Tam CS, et al. N Engl J Med. 2018;378(13):1211-23.

AIM Trial:Ibrutinib + Venetoclax for R/R MCL Results

Handunnetti SM, et al. Blood. 2019;134(suppl 1):756.; Tam CS, et al. N Engl J Med. 2018;378(13):1211-23.

100

90

80

70

60

50

40

30

20

10

00 6 12 18 24 30 36

Months

100

90

80

70

60

50

40

30

20

10

00 6 12 18 24 30 36

Months

Median PFS: 29 months Median OS: 32 months

PFS

%

OS

%

Waldenström Macroglobulinemia (WM)

American Cancer Society. cancer.org/cancer/waldenstrom-macroglobulinemia/about/key-statistics.html. Published July 19, 2018. Accessed June 2, 2020.; Castillo JJ, Treon SP. Leukemia. 2019;33(11):2555-62.; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma v1.2020.


• Incidence:• < 1% of NHL; 100-1500 new cases/year

• Deaths:• 60% OS at 5 years


• Hallmark: • MYD88L265P (> 90%), high IgM

• Prognostic factors:• MYD88WT and CXCR4 mutations

• Presentation• Hyperviscosity, neuropathy, adenopathy or

organomegaly, amyloidosis, cryoglobulinemia, cold agglutin disease, and cytopenias

WM Treatment 2020

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: WaldenströmMacroglobulinemia/Lymphoplasmacytic Lymphoma v1.2020.; Vaxman I, Gertz M. Leuk Lymphoma. 2020;1-13.

• Bulky disease• Profound cytopenias• Constitutional symptoms• Hyperviscosity symptoms

Hyperviscosity symptoms

Yes No

Plasmapheresis

BRIbrutinib ± ritixumab*

DRC (if no need for fast response)BDR (no baseline neuropathy)

PN, peripheral neuropathy.

^Patients with MYD88WT and/or CXCR4 mutations have lower and slower responses.

First line:Significantly symptomatic

Relapsed/refractory> 3 years from previous therapy

Yes No

Repeat originaltherapy

BTK inhibitor*^• Ibrutinib• AcalabrutinibBDR if baseline PN < grade 2*BR*DRC*

*If not previously received

Revisited: Pathophysiology and Mechanism of Action in WM

Adapted from Baron M, et al. Curr Oncol Rep. 2019;21(3):27.; Marini BL, et al. J Oncol

Pharm Pract. 2017;23(7):502-17.; Munshi M, et al. Blood Cancer J. 2020;10(1):12.

BCR

CD

79

a

CD

79

b

BTKPLCγ2

PKC

MAPK/MEK/ERKpathway

NF-kβpathway

LYN

SYK

TLRs

IL-6R

Microenvironment releases IL-6CXCR12/CXCR4

MYD88

HCK

iNNOVATE Trial: Study Schema

Dimopoulos MA, et al. N Engl J Med. 2018;378(25):2399-410.

Study design

• Phase III, multicenter, placebo-controlled, RCT

Primary outcome

• PFS

Ibrutinib + rituximabIbrutinib 420 mg PO daily

Rituximab 375 mg/m2 IV on day 1 of weeks 1-4 and 17-20

Rituximab + placeboRituximab 375 mg/m2 IV on day 1 of

weeks 1-4 and 17-20

n = 75

n = 75

Population• Patients with WM• Serum IgM > 0.5 g/dL• Not refractory to

rituximab or no rituximab in 12 months before study

Randomized 1:1

Cross-over allowed

Ibrutinib/placebo until progression

IgM, immunoglobulin M.

iNNOVATE Trial: ResultsIbrutinib + Rituximab vs. Rituximab for First-Line WM

0102030405060708090

100

Pat

ien

ts R

esp

on

din

g (%

)

20%

47%

Ibrutinib-R(n = 75)

92% ORR

Rituximab(n = 75)

15%

27%

47% ORR

4%

23%

3%

1%

IgM Levels

Months

Me

an Ig

M (

g/lit

er)

12106420 80

10

20

30

40

Rituximab

Ibrutinib + Rituximab

Minor responsePartial response

Very good partial responseComplete response

Dimopoulos MA, et al. N Engl J Med. 2018;378(25):2399-410.

iNNOVATE Trial: ResultsIbrutinib + Rituximab vs. Rituximab for First-Line WM

PFS

Ibrutinib-RPlacebo-Rituximab

0

Months

36302418126

PFS

(%

)

100

80

60

40

20

0

Led to FDA approval in WM

Ibrutinib + rituximab improves PFS over rituximab alone• Median PFS: NR vs. 20.3 months; HR

0.2 (95% CI, 0.11-0.38); p < 0.001

Conclusions

Patients with mutations in CXCR4 or MYD88WT have lower and slower responses

• 30-month PFS: 82% vs. 28%• 30-month OS: 94% vs. 92%

HR, hazard ratio; NR, not reached. Dimopoulos MA, et al. N Engl J Med. 2018;378(25):2399-410.

ACE-WM-001 Trial: Study Schema

Study design


Primary endpoint

• ORR

Owen RG, et al. Lancet Haematol. 2020;7(2):e112-21.

Acalabrutinib100 mg PO BID in 28-day cycles


n = 14 (TN)n = 92 (R/R)

Population• R/R WM*• No notable CVD**• No prior BTK inhibitors

*Or treatment-naïve patients who declined or had comorbidities that would preclude treatment with chemoimmunotherapy, such as symptomatic hyperviscosity with ≥ IgM 5000 mg/dL, or disease-related neuropathy

**Uncontrolled or symptomatic arrhythmias, CHF, or MI within 6 months of screening; any class 3 or 4 cardiac disease as defined by the NYHA Functional Classification; or QTc > 480 ms; patients with previous or concurrent atrial fibrillation could participate.

TN=Treat Naive

ACE-WM-001 Trial: ResultsAcalabrutinib for WM

0102030405060708090

100

Pat

ien

ts R

esp

on

din

g (%

)

14%

79%

Treatment naïve(n = 14)

93% ORR

R/R(n = 92)

13%

72%

93% ORR

Best response by line of therapy

9%

Minor responsePartial responseVery good partial response

0102030405060708090

100

Pat

ien

ts R

esp

on

din

g (%

)

14%

69%

MYD88L265P

(n = 36)

94% ORR

MYD88WT

(n = 14)

14%

64%

79% ORR

Best response by MYD88 status

11%

Owen RG, et al. Lancet Haematol. 2020;7(2):e112-21.

Tam C, et al. J Clin Oncol. 2020;(38 suppl):abstr 8007.

ASPEN Trial: Study Schema

Zanubrutinib160 mg PO BID

n = 99

n = 26

Population• R/R WM or treatment-

naïve not candidate for chemoimmunotherapy

• ECOG 0-2• MYD88MUT

Randomized 1:1


Zanubrutinib160 mg PO BID

n = 102

Cohort 2• MYD88WT

Untilprogression

Study design


Primary outcome• Complete response or very good partial response (superiority)

Future Directions: ASPEN TrialZanubrutinib vs. Ibrutinib for WM

Minor responsePartial responseVery good partial response

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts R

esp

on

din

g (%

)

16.7%

49%

Zanubrutinib(n = 102)

94.1% ORR

Ibrutinib(n = 99)

15.2%

58.6%

92.9% ORR

19.2%28.4%

First randomized trial comparing 2 BTK inhibitors

No significant differences in ORR, PFS, or OS

Look for Future FDA Guidance

Conclusions

Improved toxicity profile with zanubrutinib (not shown)

Tam C, et al. J Clin Oncol. 2020;(38 suppl):abstr 8007.

Follicular Lymphoma (FL)

Al-Hamadani M, et al. Am J Hematol. 2015;90(9):790-5.; Federico M, et al. .J Clin Oncol. 2009;27(27):4555-62.; Junlen HR, et al. Leukemia. 2015;29(3):668-76.; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas v1.2020.; Solal‐Celigny P, et al. Blood. 2004;104:1258-65.; Swerdlow SH, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2008. IARC Press.


• Incidence:• 22% of NHL

• Deaths:• 60% OS at 10 years


• Hallmark: • BCL2 translocation; t(14;18)

• Prognostic factors:• FLIPI Score, Grade 3 histology

• Presentation• Heterogenous (can be asymptomatic)

• B-symptoms, diffuse lymphadenopathy, bone marrow involvement, splenomegaly, other extra nodal sites

Current Treatment Landscape in FL

Diagnosis

Asymptomatic /No indication

“Watch and wait”Anti-CD20 mAbISRT

Mild symptoms Low tumor burden

High tumor burden

Anti-CD20 mAbISRT

Anti-CD20 mAb +• Bendamustine• CHOP• CVP• Lenalidomide+/- anti-CD20 mAb maintenanceRadioimmunotherapy

Factors to consider: patient preference and tumor burden

Factors to consider: patient age and comorbidities

Factors to consider: patient age and comorbidities

Relapsed/Refractory *Rule out histologic transformation to DLBCL

Factors to consider: response and duration of response to previous therapy, patient age, and comorbidities

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. B-cell Lymphomas v1.2020.

Anti-CD20 mAb +• Bendamustine• CHOP• CVP

+/- anti-CD20 mAb maintenanceRadioimmunotherapyLenalidomide +/- anti-CD20 mAbPI3K inhibitors (2 or more prior therapies)• Idelalisib, copanlisib, duvelisib

ISRT, involved-site radiation therapy.

PI3K Inhibitor Mechanism of Action

PI3K

AKT

mTOR

NF-kβpathway

PI3K Inhibitors

p110Isoform

Function1-4 Idelalisib

(IC50, nM)5

Duvelisib

(IC50, nM)6

Copanlisib

(IC50, nM)7

α Glucose homeostasis 820 1602 0.5

β Platelet aggregation 565 85 3.7

γT-cell and granulocyte

function89 27.4 6.4

δB and T lymphocyte

function2.5 2.5 0.7

1. Sopasakis VR, et al. Cell Metab. 2010;11(3):220-30.; 2. Jackson SP, et al. Nat Med. 2005;11(5):507-14.; 3. Sasaki T, et al. Science. 2000;287(5455):1040-6.; 4. Okkenhaug K, et al. Science. 2002;297(5583):1031-4.; 5. Lannutti BJ, et al. Blood. 2011;117(2):591-4.; 6. Göckeritz E, et al. Int J Cancer. 2015;137(1):2234-42.; 7. Marini BL, et al. J Oncol Pharm Pract. 2017;23(7):502-7.

BCR

CD

79

a

CD

79

bLYN

SYK

PI3K Inhibitor Pivotal Trial Design

Double refractory NHL (failed to respond or relapsed within 6

months following rituximab and an alkylator)

Idelalisib 150 mg PO BID (N = 72 FL) Primary endpoint: ORR

Single-arm, open-label, phase 2 study

Refractory to both rituximab and chemotherapy or RIT

Previously received an alkylating agent or purine analogue

Continuous until disease progression or unacceptable toxicity

Duvelisib 25 mg PO BID (N = 83 FL) Primary endpoint: ORR


Relapsed or refractory after 2 or more lines of therapy

Copanlisib 60 mg IV over 60 minutes on days 1, 8, and 15 of 28-day cycle (N = 104 FL)

Primary endpoint: ORR


Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Dreyling M, et al. Am J Hematol. 2020;1-10.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. N Engl J Med. 2014;370(11):1008-18.; Salles G, et al. Haematologica. 2017;102(4):e156-9.

Efficacy Outcomes: PI3K Inhibitors R/R FL

0

20

40

60

14% CR

42% PR

17% CR

44% PR

1.2% CR

41% PR

Idelalisib DuvelisibCopanlisib

Re

spo

nse

Rat

es

56% ORR61% ORR

42.2% ORR


Efficacy Outcomes: PI3K Inhibitors R/R FL

Idelalisib Duvelisib Copanlisib

10.8 months (range, 0-26.9)

2.6 months (range, 1.6-11)

Median time to response

Median duration of response

1.7 months (range, 1.3-9.7)

1.87 months (range, 1.4-11.7)

14.1 months (range, 0-42.5)

10 months (range, 6.3-10.5)

1686420 10 12 14Months


Adverse Effect Management and Patient Monitoring Plans

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Diarrhea(All grades)

Diarrhea(Grade ≥ 3)

Atrial fibrillation(All grades)

Hypertension(Grade ≥ 3)

Bleeding(Grade ≥ 3)

Arthralgia/Myalgia(All grades)

Infection(Grade ≥ 3)

Headache (Allgrades)

Ibrutinib Acalabrutinib Zanubrutinib

Adverse EffectBrukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Imbruvica (ibrutinib) [prescribing information]. 2020.;Rule S, et al. Haematologica. 2019;104(5):e211-e4.; Tam CS, et al. Hematol Oncol; 2019;37:245-7.; Wang M, et al. Lancet. 2018;391(10121):659-67.

*Data are comparisons from separate trials in patients with MCL

Inci

de

nce

BTK Inhibitors: Select Adverse Events (AEs) Across Pivotal Trials*

Off-Target Effects

Berglӧf A, et al. Scand J Immunol. 2015;82(3):208.; Bose P, et al. Expert Opin Drug Metab Toxicol. 2016;12(11):1381-92.; Bye AP, et al. Blood Adv. 2017;1(26):2610-23.; Ghez D, et al. Blood. 2018;131(17):1955-9.; Rogers K. Blood. 2018;131(17):1882-4.; Rogers KA, et al. Leukemia. 2019;33(10):2527-30.; Ruchlemer R, et al. Mycoses. 2019;62(12):1140-7.; Shatzel JJ, et al. J Thromb Haemost. 2017;15(5):835-47.; Woyach JA. Blood. 2018;132(18):1869-70.

EGFR

SRC

TEC

ITK

JAK3

BMX

ERBB4

Rash, cardiac toxicity, diarrhea

Platelet effects

Cardiac toxicity

Antibody-dependent cellular cytotoxicity, migration of PMN

Immune effects

Platelet effects, T-cell priming

Cardiac toxicity

PMN, polymorphonuclear leukocyte.

ASPEN Trial: Adverse EffectsOnly Randomized Trial Comparing BTK inhibitors

0%

10%

20%

30%

40%

50%

60%

70%

80%

Atrial Fibrillation(All Grades)

MinorBleeding

MajorBleeding

Diarrhea(All Grades)

Infection Pneumonia Hypertension Neutropenia Thrombocytopenia

Zanubrutinib Ibrutinib

Inci

de

nce

(%

)

Tam C, et al. J Clin Oncol. 2020;38(suppl):abstr 8007.

BTK Inhibitors: Hypertension and Atrial Fibrillation

Hypertension

• Risks include cardiac risk factors, acute infections, prior history of AF

• Educate patient on risk for AF and what to do in the event of abnormal heart rhythm

• AF is not an absolute contraindication to continuing BTK inhibitors

• Be cautious of drug interactions when managing AF (i.e., diltiazem and CYP3A4)

• Anticoagulation can be used but should be used with caution

• Avoid vitamin K antagonists

• If AF persists, consider the risks and benefits of treatment and dose modification

Atrial fibrillation (AF)

• Risks include cardiac risk factors, prior history of hypertension

• Monitor blood pressure throughout treatment

• Hypertension is not an absolute indication to discontinue BTK inhibitors

• Adequate management of hypertension from BTK inhibitors mitigates cardiovascular events

• If hypertension is persistent or life threatening, consider risks and benefits of treatment and dose modification

Brukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Dickerson T, et al. Blood. 2019;134 (22):1919-28.; Imbruvica (ibrutinib) [prescribing information]. 2020. CYP, cytochrome P450.

BTK Inhibitors: Mechanism of Bleeding

Bye AP, et al. Blood Adv. 2017;1(26):2610-23.

SFK

TEC/BTK

Secondary mediators

αIIbβ3 activation and

granule secretion

Ibrutinib Acalabrutinib

Aggregation, adhesion, andstable thrombus formation

CLEC-2

GPIb

• BTK, SFK (src family kinases), and TEC are involved in several platelet activation and adhesion functions:

• GPVI, CLEC-2, GPIb, integrin αIIbβ3

• TEC compensates when BTK is inhibited/dysfunctional

• BTK inhibition alone leads to mildly diminished platelet activation

• Blocking both BTK and TEC leads to significant platelet inhibition, platelet aggregation, and thrombus stability

GPVI

vWFCollagen

Reversible impact on platelet aggregation within 1 week of discontinuation

Dose reduction may mitigate platelet aggregation and improve bruising

Recommend holding BTK inhibitor prior to and after invasive procedures for 3 (minor) to 7 days (major)

Blood thinner or antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor) increase bleeding risk

Anticoagulants increase bleeding risk by impacting multiple hemostatic pathways

Anticoagulants are not contraindications

Avoid concurrent vitamin K antagonists

Clinical Pearls and Management

Major bleed (grade ≥ 3) N=13

Total 18%

Antiplatelet + anticoagulant 54%

Antiplatelet alone 30%

Anticoagulant alone 8%

Interacting medication 8%

None of the above 0%

Real-world risk*

*Data represented are for ibrutinib.

Imbruvica (ibrutinib) [prescribing information]. 2020.; Kunk PR, et al. Blood. 2016;128(22):3229.

BTK Inhibitors:Bleeding and Bruising Management

Brukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Imbruvica (ibrutinib) [prescribing information]. 2019.; Rule S, et al. Haematologica. 2019;104:e211-4.; Tam CS, et al. Hematolog Oncol. 2019:37:245-7.; Wang M, et al. Lancet. 2018;391:659-67.

Muscle cramps

Oral magnesium supplements

Arthralgias/myalgias

Acetaminophen, prednisone, tonic water

Reduce dose of BTK inhibitor or therapy discontinuation

Leg lymphedema

Therapy discontinuation

Fatigue

Reduce dose of BTK inhibitor or therapy discontinuation

Headaches

Acetaminophen, caffeine, hydration

Rash

Topical emollients or corticosteroids can alleviate symptoms

Diarrhea

If no evidence of infection, antidiarrheals as needed

Infection

Monitor and treat as needed

For all grade 3/4 non-hematologic AEs: hold BTK inhibitor until resolution to baseline or grade 1

Resume at original dose for first recurrence, refer to package insert for specific dose reductions for second recurrence

BTK Inhibitors: Miscellaneous AE Management

Venetoclax: AEs and Management

Wk 1

Wk 2

Wk 3

Wk 4

Wk 5Pertinent AEs: Diarrhea (all grade): 43% Nausea (all grade): 42% Neutropenia (grade ≥ 3): 45% Tumor lysis syndrome (TLS)

20 mg 50 mg 100 mg 200 mg 400 mg

Assess risk: inpatient for first dose of first 2 ramp-up doses if high risk (i.e., bulky adenopathy per PI)

Monitor: TLS labs per PIPrevention: hydration, antihyperuricemic agents

Treatment: per institutional guideline

Ven

clex

ta(v

enet

ocl

ax)

[pre

scri

bin

g in

form

atio

n].

20

19

.

PI,

pre

scri

bin

g in

form

atio

n.

Venetoclax: TLS Management

TLS risk Disease characteristics

Low risk No bulky adenopathyALC < 25 x 109/L

Intermediate risk Bulky adenopathy: ≥ 5 cm and < 10 cmorALC: ≥ 25 x 109/L

High risk Bulky adenopathy: ≥ 10 cmorBulky adenopathy: ≥ 5 cm and ALC ≥ 25 x 109/L

Additional factors to consider: baseline uric acid, LDH, potassium, phosphorous, SCr, calcium

Assess Risk

TLS risk Management plan

Low risk Outpatient: • Oral hydration (1.5-2 L per day) and allopurinol• Lab monitoring: pre-dose and 6 to 8 hours & 24

hours after first dose of 20 mg and 50 mg and then pre-dose at subsequent ramp-up doses

Intermediate risk Outpatient: • Oral hydration (1.5-2 L per day), IV (PRN), and

allopurinol• Lab monitoring: pre-dose, 6 to 8 hours & 24 hours

after first dose of 20 mg and 50 mg and then pre-dose at subsequent ramp-up doses

• If creatinine clearance < 80 mL/min, consider inpatient admission for first 2 dose escalations

High risk Inpatient for first dose of first 2 ramp-up doses:• Oral hydration and IV as tolerated• Allopurinol (consider rasburicase based on

baseline uric acid)

Develop a Management Plan2

Venclexta (venetoclax) [prescribing information]. 2019.

1

ALC, absolute lymphocyte count; LDH, lactate dehydrogenase; PRN, as needed; SCr, serum creatinine.

0

10

20

30

40

50

60 Idelalisib Duvelisib Copanlisib

*Data are comparisons from separate trials in patients with FL

Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. New Engl J Med. 2014;370(11):1008-18.

Inci

den

ce (

%)

PI3K Inhibitors:Select Grade ≥ 3 AEs Across Pivotal Trials*

Immune-related toxicity mechanism: decrease in T-regulatory cells (due to PIK3δ inhibition)

HepatotoxicityDiarrhea and colitisIntestinal perforationInfectionPneumonitis

Diarrhea and colitisInfectionPneumonitisCutaneous reactions

None


PI3K Inhibitors:Black Box Warnings

• Febrile neutropenia: 3%• 21% experienced a fatal

or serious infection• Pneumocystis jirovecii

pneumonia (PJP) orcytomegalovirus (CMV): < 1% of patients

• Pneumonitis: 2%

• Febrile neutropenia: 9.3%• 31% experienced a fatal or

serious infection• PJP or CMV: 1% of patients,

1 case of bronchopulmonary aspergillosis

• Pneumonitis: 5%

• Neutropenia (including febrile neutropenia): 32%

• 19% experienced a fatal or serious infection

• PJP: < 1% of patients, 1 case of bronchopulmonary aspergillosis

• Pneumonitis: 5%


Aliqopa (copanlisib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. New Engl J Med. 2014;370(11):1008-18.; Zydelig (idelalisib) [prescribing information]. 2018.

PI3K Inhibitors:Infectious and Respiratory Complications

Management

PneumonitisInfection

Provide PJP prophylaxis during treatment

Clinical and laboratory monitoring for CMV infection is recommended in patients with history of CMV infection or positive CMV serology at the start of treatment

Suspected infection, CMV viremia/infection, or PJP infection: interrupt therapy until infection has resolved. Permanent discontinuation if PJP infection is confirmed, consider permanent discontinuation for all infections.

Pneumonitis: Time to onset ranged from < 1 to 15 months

Monitor for pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation

Discontinue therapy with any severity symptomatic pneumonitis and initiate appropriate treatment with corticosteroids

Aliqopa (copanlisib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. New Engl J Med. 2014;370(11):1008-18.; Zydelig (idelalisib) [prescribing information]. 2018.

PI3K Inhibitors:Infectious and Respiratory Complications

7 months (range, 0.5-29.8 months)

1.5 months (range, 0-15.2 months)

Mild to moderate diarrhea

2724211815129630 30

Severe diarrhea

*Mild: increase of < 4 stools per day over baseline; Moderate: increase of 4-6 stools per day over baseline

*Severe: increase of ≥ 7 stools per day over baseline

Patient and provider education

Mild diarrhea: initiate supportive therapy with antidiarrheal agents, monitor weekly until resolved

Mild diarrhea unresponsive to intervention and moderate diarrhea: withhold therapy, initiate supportive therapy with enteric-acting steroids (e.g., budesonide); once resolved, resume therapy at reduced dose

Severe diarrhea or abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs: withhold therapy, initiate supportive therapy with enteric-acting steroids or systemic steroids; once resolved, consider resuming therapy at reduced dose

For any recurrent grade 3+ diarrhea or colitis, permanently discontinue therapy

Time to onset (months)

Management

Aliqopa (copanlisib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Coutré SE, et al. Leuk Lymphoma. 2015;56(10):2779-86.; Zydelig (idelalisib) [prescribing information]. 2018.

PI3K Inhibitors:Diarrhea and Colitis Management

• Peak: 5-8 hours post-infusion• Permanent BG elevation in approximately 18% of patients, 10% of patients will develop A1C > 6.5%• Optimize BG control in all patients before starting copanlisib

Pre-dose: fasting BG > 160 mg/dL OR

random/non-fasting BG > 200 mg/dL

• Withhold until FBG ≤ 160 mg/dL or a random/non-fasting BG ≤ 200 mg/dL

• Close observation with PCP or endocrinology

Pre-dose or post-dose BG ≥ 500 mg/dL or more

• Withhold until FBG ≤ 160 mg/dL or a random/non-fasting BG ≤ 200 mg/dL or less, then reduce dose

• Close observation with PCP or endocrinology• If persists at lowest dose, permanently discontinue

Management

Transient hyperglycemia

Aliqopa (copanlisib) [prescribing information]. 2019.; Cheson BD, et al. Clin Lymphoma Myeloma Leuk. 2019;19(3):135-41.

A1C, hemoglobin A1C; BG, blood glucose; FBG, fasting blood glucose; PCP, primary care physician.

PI3K Inhibitors:Hyperglycemia Management

• Monitor BP pre- and post-dose

• BP decline starting 2 hours post-infusion but can remain elevated for 6-8 hours

• Optimal BP control should be achieved before starting each infusion

Pre-dose BP ≥ 150/90 mmHg

• Withhold until BP is < 150/90 mmHg based on 2 consecutive BP measurements at least 15 minutes apart

Post-dose BP≥ 150/90 mmHg

(non-life-threatening)

• If antihypertensive is not required, continue at previous dose

• If antihypertensive is required,* consider dose reduction

• Discontinue therapy if BP remains high (> 150/90 mmHg) despite antihypertensive

Post-dose elevated BP (life threatening)

• Permanently discontinue

ManagementTransient hypertension

*Decision to treat should be individualized on the basis of several factors, including baseline BP, severity of BP elevation, and pre-existing cardiovascular risk (diabetes, chronic kidney disease) or coronary vascular disease.

If treating during the infusion, short-acting antihypertensives should be used

Aliqopa (copanlisib) [prescribing information]. 2019.; Cheson BD, et al. Clin Lymphoma Myeloma Leuk. 2019;19(3):135-41. BP, blood pressure.

PI3K Inhibitors:Hypertension Management

SPDlymph node size

0 1 2 3 4 5 6 7 8 9 10 11

550

450

350

250

150

50

-50

Absolute lymphocyte count

Month Month

-100

-75

-50

-25

0

25

Mea

n P

erce

nt

Ch

ange

fro

m B

asel

ine

0 1 2 3 4 5 6 7 8 9 10 11

Blood Lymphocytes Lymph Nodes

Bro

wn

JR

, et

al. B

loo

d. 2

01

5;1

26

(23

):2

95

2.;

Byr

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. New

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Med

. 20

13

;36

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2-4

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SPD

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Transient Lymphocytosiswith PI3K Inhibitors/BTK Inhibitors?

Summary of Novel Agents in Lymphoma

FDA approval Class Dose SuppliedRouteAgent

IbrutinibCLL (1st+), MCL (2nd+)WM (1st+), MZL (2nd+)

BTKiMCL: 560 mg dailyCLL: 420 mg daily

Oral70-, 140-, 280-, 420-, and 560-mg tablets

AcalabrutinibMCL (2nd+)CLL (1st+)

BTKi 100 mg twice daily Oral 100-mg capsule

Zanubrutinib MCL (2nd+) BTKi160 mg twice daily or320 mg daily

Oral 80-mg capsule

IdelalisibCLL (3rd+), FL (3rd+)CLL with comorbidities (2nd+)

PI3Ki (δ) 150 mg twice daily Oral100- and 150-mgtablets

Duvelisib PI3Ki (γ/δ) 25 mg twice daily Oral15- and 25-mgcapsules

Copanlisib FL (3rd+) PI3Ki (α/δ)60 mg IV over 1-hour days 1, 8, and 15 (28-day cycle)

Intravenous 60 mg vial

Venetoclax CLL (1st+) BCL2i MCL: 400-800 mg with foodCLL: 400 mg with food

Oral10-, 50-, and 100-mg tablets

CLL (3rd+), FL (3rd+)

Aliqopa (copanlisib) [prescribing information]. 2019.; Brukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Imbruvica (ibrutinib) [prescribing information]. 2020.; Zydelig (idelalisib) [prescribing information]. 2018.

Drug and Comorbidity Interactions with Novel Agents in Lymphoma

*Avoid proton pump inhibitors; take acalabrutinib 2 hrs before H2RAs and antacids (reduces acalabrutinib AUC 40% to 50%). †Idelalisib inhibits CYP3A4 (strong) and UGT1A1. Duvelisib inhibits CYP3A4 (moderate); all agents listed inhibit P-glycoprotein except for acalabrutinib, copanlisib, and duvelisib.

IbrutinibCYP3A4 (major)CYP2D6 (minor)

Voriconazole: ↓ 140 mg daily?Posaconazole: ↓ 70 mg dailyModerate: ↓ 280 mg daily

Avoid No changesChild-Pugh A: ↓ 140 mgChild-Pugh B: ↓ 70 mgChild-Pugh C: avoid

*AcalabrutinibCYP3A4 (major)P-gp, BCRP

Strong: avoidModerate: ↓ 100 mg daily

↑ 200 mgtwice daily

No changesNo changesMonitor in severe

Zanubrutinib CYP3A4 (?)Strong: ↓ 80 mg dailyModerate: ↓ 80 mg twice daily

Avoid No changesSevere: ↓ 80 mgtwice daily

**IdelalisibCYP3A4 (major)P-gp, UGT1A4

Avoid Avoid No changesCaution(1.7x increase AUC)

^Duvelisib Strong: ↓ 15 mg daily Avoid No changes No changes

CopanlisibCYP3A4 (major)P-gp, BCRP

Strong: avoid or↓ 45 mg daily

Avoid No changesChild-Pugh B: ↓ 45 mgChild-Pugh C: avoid

VenetoclaxCYP3A4 (major)P-gp

Strong: avoid during ramp-up,↓ 75% thereafterModerate: ↓ 50%

Avoid Monitor TLS Monitor toxicity

CYP3A4 (major)

Metabolism CYP Inhibitors CYP Inducers HepaticRenalAgent

AU

C, a

rea

un

der

th

e cu

rve;

H2

RA

, his

tam

ine

-2 r

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tor

anta

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TLS

, tu

mo

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sis

syn

dro

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Aliq

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20

19

.; B

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(zan

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) [p

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]. 2

01

9.;

Cal

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ence

(aca

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) [p

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]. 2

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9.;

Co

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[pre

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20

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.; I

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2

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01

8.

Considerations When Selecting Therapies

Molecular mutations

Patient preference

Cytogenetics Line of therapy

Age/fitnessDrug

interactions

AE profile (including

financial toxicity)

Dosing schedule

ComorbiditiesResponse to

previous therapy

Patient Education

Administration

Adherence

Drug-drug interactionsContact with new medications, herbals, or supplements

Create a monitoring planHighlight key adverse effects, how to self-manage, and when to report

Drug procurement

Thank You!

new directions for oral treatment in b-cell malignancies · 2020. 8. 18. · oral therapy for the...

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